Novel class of acyl-derivatives of carnitine, process for preparing same and therapeutic use thereof

ABSTRACT

A novel class of acyl-derivatives of carnitine is disclosed wherein the acyl radical is either the radical of unsaturated organic acids (typically, acrylic acid) or the radical of saturated organic acids substituted with tert-alkyl, cycloalkyl, cycloalkenyl, alkoxyl, heterocyclic and carboalkoxylradicals, or with aldehyde or hydroxy groups. These acyl-derivatives of carnitine are useful therapeutical agents in the treatment of cardiac disorders, hyperlipidaemias and hyperlipoproteinaemias.

This is a division of Ser. No. 068,748, filed on June 30, 1987, now U.S.Pat. No. 4,766,222, which is a continuation of Ser. No. 753,653, filedJuly 10, 1985, now abandoned, which is a continuation of Ser. No.433,427, filed Oct. 8, 1982, now abandoned, which is a continuation ofSer. No. 237,312, filed Feb. 23, 1981, now abandoned.

The present invention relates to a novel class of acyl-derivatives ofcarnitine (β-hydroxy γ-butyrobetaine), a process for preparing same andthe therapeutical utilization thereof.

More particularly, the present invention relates to acyl-derivatives ofcarnitine having general formula ##STR1## wherein: X⁻ is an anion,preferably a halogenide or sulfate anion, and

R is the radical of the following organic acids:

(a) unsaturated organic acids: acrylic, vinyl-acetic and allyl-aceticacid;

(b) saturated organic acids substituted with a tert-alkyl radical:tert-butyl acetic and tert-butyl propionic acid;

(c) saturated organic acids substituted with a cyclo-alkyl radical:cyclopentan-carboxylic, cyclopentan-acetic, cyclopentan-propionic,cyclohexyl-acetic and cyclohexyl-butyric acid;

(d) saturated organic acids substituted with a cycloalkenyl radical:3-cyclohexene-carboxylic and 2-cyclopenten-acetic acid; (e) saturatedorganic acids substituted with an alkoxyl-radical: methoxy acetic andethoxy acetic acid;

(f) saturated organic acids substituted with a carboalkoxyl radical:3-carbomethoxy propionic and 4-carbomethoxy butyric acid;

(g) hydroxy-substituted saturated organic acids: 2-hydroxy isobutyric,2-hydroxy isovaleric, 2-hydroxy isocaproic, 2-hydroxy-2-methyl butyric,2-methyl-3-hydroxy-propionic, 2-hydroxy-tert-butyl-acetic,3-hydroxy-3-methyl-glutaric (monoester), 3-hydroxy-2-methyl-glutaric(monoester) and 3-hydroxy-propionic acid;

(h) saturated organic acids substituted with an aldehyde group: 2-formylpropionic and formyl-isobutyric acid;

(i) saturated organic acids substituted with a heterocyclic radical:1,2-dithiolane-3-pentanoic, 2-thiophene-carboxylic and 2-thiopheneacetic acid.

The present invention encompasses the compounds of formula (I) both intheir optically active forms (either D or L) and in their racemic form(D,L) and also encompasses their pharmacologically acceptable salts,whether they are optically active or inactive.

The compounds of formula (I) can in fact be prepared either as such orin the form of salts with mineral acids or with mono- ormulti-carboxylic aliphatic and aromatic acids or with sulfonic andsulfamic acids. Generally, the compounds of formula (I) and theircorresponding pharmacologically acceptable salts have shown remarkablecardiotroopic, hyperlipoproteinaemic and hyperlipidaemic activities.

The compounds of formula (I) are normally prepared in the form ofchlorides.

It is in fact preferable to react β-hydroxy γ-butirobetaine chloridewith the acid chloride of the appropriate acid (a) through (i)previously mentioned.

The process for preparing these novel acyl-derivatives normally takesplace at a temperature comprised between 0° C. and 80° C. in ananhydrous environment and in the presence of an organic solvent selectedfrom the group consisting of trifluoroacetic acid and the acids (a)through (i) previously listed under formula (I) corresponding to theused acid chloride. When the acid chloride is solid and is not easilysoluble in said organic solvent it is possible to improve its solubilityin such a way as to obtain a homogeneous phase by adding a small amountof a chlorinated solvent, such as chloroform or anhydrous methylenechloride.

Particular care will be taken in order to maintain anhydrous theenvironment by protecting the reaction system with suitable dehydratingmeans, e.g. CaCl₂ --containing tubes.

At the end of the reaction the resulting mixture is cooled and usuallytreated with acetone; the solid, if any, which separates is removed,whereas the precipitate which forms by adding ethyl ether is collected.

The precipitate can be purified by crystallization with ethyl ether.Generally one or two crystallizations are sufficient to obtain a highpurity product which can be easily checked by thin layer chromatography(T.L.C.) using silica plates and various eluents such as CHCl₃--MeOH-conc. NH₄ OH (50:30:8 v/v) or n-BuOH-- acetic acid --H₂ O(60:20:20: v/v).

Generally, the reaction yields range from 60 to 85%, on condition thatthe yield lowering, if any, which might take place during thepurification by crystallization is not taken into consideration.

The following examples, beside setting forth several chimico-physicaldata of some compounds of this invention, illustrate the synthesisprocess thereof without limiting the invention scope.

EXAMPLE 1 Preparation of tert-butyl acetyl carnitine chloride ##STR2##

Carnitine chloride (1.97 g; 0.01 moles) was dissolved in trifluoroaceticacid (10 cc). To the solution tert-butyl acetyl chloride (1.4 cc; 0.01moles) was slowly added under stirring. The resulting mixture was keptunder stirring at room temperature for 48 hours. To te mixture Et₂ O wasadded and the thus obtained precipitate was filtered off. The rawproduct was crystallized from isopropanol-ethyl ether, thus obtaining apure product. MP 164°-165° C.

Yield 80%. ##STR3##

EXAMPLE 2 (a) Preparation of cyclohexyl acetyl chloride ##STR4##

Cyclohexyl acetic acid (2.5 g; 0.02 moles) was mixed with SOCl₂ (3.7 cc;0.05 moles) and the resulting solution was kept at 80° C. for 1.5 hours.The mixture was concentrated under vacuum and some washings were carriedout with anhydrous toluene to remove SOCl₂. The mixture was then driedunder vacuum and the title product was obtained as a raw material whichwas used as such in the next step (b).

(b) Preparation of cyclohexyl acetyl carnitine chloride ##STR5##

Carnitine chloride (2.97 g; 0.01 moles) was dissolved in trifluoroacetic acid (10 cc). To this solution was added cyclohexyl acetylchloride (0.01 moles) prepared as previously disclosed and the resultingmixture was kept under stirring for 48 hours. Ethyl ether was then addedand the resulting mixture was kept under stirring for 0.5 hours at 0° C.A precipitate was obtained, which was filtered off and dried undervacuum.

MP 161°-162° C., yield 70%. ##STR6##

EXAMPLE 3 Preparation of cyclopentanpropionyl carnitine chloride

Carnitine chloride (1.97 g; 0.01 moles) was dissolved in trifluoroaceticacid (10 cc). To the resulting solution 3-cyclopentanpropionyl chloride(1.60 g; 0.01 moles) was slowly added under stirring. The resultingmixture was kept under stirring at 45° C. overnight. The mixture wasthen cooled, acetone (40 ml) was added and the mixture was kept understirring for 2 hours in ice. The precipitate thus formed was filteredoff and to the filtrate ethyl ether was added. The white solid whichprecipitated was dissolved in ethanol-acetone (5:1) and once againprecipitated with ether.

M.P. 170°-172° C., yield 90%.

    ______________________________________                                        NMR (D.sub.2 O)                                                                        δ 5.5                                                                                ##STR7##                                                         2.8         (d, 2H, NCH.sub.2)                                                3.2         (s, 9H, (CH.sub.3).sub.3)                                         2.7         (d, 2H, CH.sub.2 COOH)                                            2.4                                                                                        ##STR8##                                                         1.9-0.9                                                                                    ##STR9##                                                ______________________________________                                    

EXAMPLE 4 Preparation of vinyl acetyl carnitine chloride ##STR10##

To a solution of carnitine chloride (2 g; 0.01 moles) in trifluoroaceticacid (6 ml) vinyl acetyl chloride (1.8 ml; 0.02 moles) was added understirring at room temperature.

The reaction mixture was then brought at 50° C. and kept under reactingconditions overnight. The mixture was then cooled to room temperatureand poured in ethyl ether (200 ml) and kept under stirring for 20minutes. The ether phase was decanted and the thus obtained precipitatewas taken up with acetonitrile and the resulting solution was allowed tostand for 2 hours. The unreacted carnitine, which separated in the formof a crystalline solide, was filtered off and to the filtrate ethylether was added. The precipitate thus formed was a white crystallinesolid.

TLC (CHCl₃ /MeOH/H₂ O/NH₄ OH, 55:35:5:5) Rf 0.55. ##STR11## In the sameNMR spectrum there were also present the following meaningful signalswhich were attributed to the isomer crotonoyl carnitine:

    δ1.95 (3H, d.d., CH.sub.3 --C═); 6.64-7.38 (2H, m, --CH═CH--).

By computation of the integrals of the foregoing signals it was possibleto evaluate the amount of said isomer which was present in the productin an amount of about 15-20%.

EXAMPLE 5 Preparation of ethoxyacetyl carnitine isobutylester

(a) Preparation of carnitine isobutylester

Carnitine chloride (10 g; 0.05 moles) was suspended in 100 ml ofisobutanol. The suspension was cooled with an ice bath and gaseous HClwas bubbled therein till complete saturation was reached. The resultingmixture was kept for 2 hours under reflux conditions. The mixture wasthen concentrated to remove the alcohol, the concentrate was dissolvedin distilled water and the solution was neutralized with IR-45 resin.The resulting product was lyophilized, thus yielding 12 g of carnitineisobutylester.

(b) Preparations of ethoxyacetic acid chloride

Thionyl chloride (1.1 cc; 0.0125 moles) was added to ethoxyacetic acid(1.3 cc; 0.012 moles). The resulting mixture was kept at roomtemperature for 12 hours. The reaction mixture was washed three timeswith a chloroform-anhydrous ethyl ether mixture and subsequentlyconcentrated under vacuum (80 mm Hg), at 30 C. 1.15 grams ofethoxy-acetic acid chloride were obtained.

(c) Reaction between carnitine isobutylester and ethoxyacetic acidchloride.

Carnitine isobutyl ester (1.1 g; 0.043 moles) was dissolved in anhydrousacetone and to the resulting solution the ethoxyacetic acid chloride(1.15 g; 0.009 moles) was added. The reaction mixture was dried and theresidue kept in an atmosphere of inert gas (argon) at room temperaturefor two days. The residue was then crystallized from isopropanol-ethylether. The title product was obtained with 65% yield.

    ______________________________________                                        T.L.C. Eluent:                                                                            CHCl.sub.3   40                                                               CH.sub.3 OH 40                                                                CH.sub.3 COONa 0.01M 10                                           NMR                                                                                        ##STR12##                                                                    4.2 (2H,s,COCH.sub.2 O); 4.0 (4H,m,                                            ##STR13##                                                                     ##STR14##                                                                    2.7 (2H, d,CH.sub.2 COO); 1.9 (1H, m,                                          ##STR15##                                                                     ##STR16##                                                        ______________________________________                                    

EXAMPLE 6 Preparation of 3-cyclohexenylcarboxylcarnitine chloride

(a) Preparation of 3-cyclohexenecarboxyl chloride.

Cyclohexenecarboxylic acid (1.2 cc; 0.01 moles) was mixed with oxalylchloride (0.9 cc; 0.01 moles) and the resulting mixture was kept understirring at room temperature for 3.5 hours. The solution was thenconcentrated under vacuum (100 mm Hg; t=70° C.). The raw product thusobtained was used as such in the next step.

(b) Reaction of 3-cyclohexenecarboxyl chloride with carnitine chloride.

Carnitine chloride (1 g; 0.05 moles) was dissolved in trifluoroaceticacid (2 cc). To the resulting solution was slowly added under stirring,at room temperature, the chloride (0.01 moles) of the previous step. Theresulting action mixture was kept under stirring for 15 hours. Ethylether was then added to the reaction mixture and a precipitate wasobtained which was subsequently twice washed with ethyl ether toeliminate the excess of acid chloride. The precipitate was filtered anddried under vacuum.

Yield: 90%.

    ______________________________________                                        T.L.C. Eluent:                                                                         CHCl.sub.3                                                                              60                                                                  MetOH     40                                                                  H.sub.2 O 15                                                                  Isopr OH  10                                                                  CH.sub.3 COOH                                                                           15                                                         NMR                                                                                  ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                              ______________________________________                                    

EXAMPLE 7 Preparation of 3-carbomethoxypropionyl carnitine chloride

To a solution of carnitine chloride (4 g; 20 m moles) in trifluoroaceticacid, 3-carbomethoxypropionyl chloride (3.0 cc; 24 m moles) was addedand the resulting reaction mixture was kept under stirring at 45° C.overnight. The mixture was then cooled and ethyl ether was added. Thesolid which formed was crystallized from iso-propanol.

M.P. 160°-161° C.

T.L.C.: CHCl₃ MeOH/CH₃ COONa 40/40/20 m.u.

NMR: D₂ O=2.75 (4H s, CH₂ --CH₂) 2.80 (2H d, CH₂ --COOH) 3.25 (9H s,(CH₃)₃) 3.70 (3H s, COOCH₃) 3.80 (2H d, N--CH₂) 5.65 (m, --CH₂--CH--CH₂)

EXAMPLE 8 Preparation of 4-carbomethoxy butyrul carnitine chloride

To a solution of carnitine (2.0 g; 10 m moles) in TFA (5 cc),4-carbomethoxy butyrul chloride (1.65 cc; 12 m moles) was added and theresulting reaction mixture was kept at room temperature under stirringfor 24 hours. To this mixture anhydrous ethyl ether was then added. Asolid formed which was filtered off and crystallized from hotisopropanol.

M.P. 130°-132° C. ##STR20##

EXAMPLE 9 Preparation of methoxy acetyl carnitine chloride

A mixture of methoxyacetic acid (3 ml; 0.04 moles) and methoxyacetylchloride (3 ml; 0.03 moles) was kept under stirring at 30° C. for 2hours. To this mixture carnitine chloride (4 g; 0.02 moles) which hadbeen previously dried was added. The resulting mixture was brought to40° C. and kept under stirring for seven days. The mixture was thentaken up with acetonitrile and the unreacted carnitine chloride wasfiltered off. Upon addition of tert-butyl methyl ether an oilprecipitated. The oil precipitation was repeated four times withacetonitrile/tert butyl methyl ether. The oil which finally separatedwas lyophilized. Four grams of mthoxy acetyl carnitine chloride werethus obtained.

Yield: 75%. ##STR21##

EXAMPLE 10 Preparation of ethoxy acetyl carnitine chloride

A mixture of ethoxy acetic acid (5 ml; 0.07 moles) and ethoxyacetylchloride (1.8 ml; 0.015 moles) which had been prepared as disclosed instep (b) of Example 5, was kept under stirring for 2 hours at 80° C. Tothis mixture carnitine chloride (2 g; 0.01 moles) which had beenpreviously dried was added. The resulting mixture was first kept at 80°C. until complete dissolution of carnitine took place, then at 40° C.for eight days. A further amount of ethoxyacetyl chloride (0.9 ml; 0.007moles) was added and the resulting mixture was kept at 40° C. for sevendays. Upon addition to the mixture of tert-butyl methyl ether an oilprecipitated. The oil precipitation was repeated four times withacetonitrile/tert butyl methyl ether until complete removal of theethoxyacetic acid in excess. 1.5 grams of the title compound were thusobtained.

Yield: 75%. ##STR22##

The characteristics of pharmacological activity of the compounds ofgeneral formula (I) are hereinbelow illustrated.

The acute toxicity of the compounds of general formula (I) wasinvestigated in mice using the Weil method (Weil C. S., Biometr. J. 8,249, 1952). The LD₅₀ values given in Table 1 below, show that thecompounds exhibit good tolerance.

The cardiokinetic effect was investigated on rabbit hearts isolated bythe Langendorff method. Rabbit hearts isolated by this method wereperfused with oxygenated Ringer solution at 38.2° C. The isometriccontractions, electro-cardiogram and coronary flow were recorded using a"Battaglia-Rangoni" polygraph. By removing the oxygen from the perfusionfluid, metabolic damage was induced in the cardiac muscle, up to an 80%reduction in the cardiac contractile force.

Under these conditions of prolonged anoxia the aerobic glycolysis of themyocardium is sowed down with attendant formation of acid catabolitesdue to both the accumulation of pyruvic acid and its conversion tolactic acid which cannot be utilized because of the depression ofpyridine enzymes, such as LDH (lactodehydrogenase). This hasrepercussions on the anaerobic glycolysis affecting an ever increasingnumber of enzymes, accompanied by a progressive and increasinglycritical exhaustion of the myocardium. Thus a whole series of cardiacmuscle fatigue levels occurs which can be observed by the behaviour ofthe examined parameters, namely the contractile force, coronary flow,heart rate and cardiac rhythm. As soon as the contractile force wasreduced by 80%, the perfusion fluid was once again oxygenated eitherwithout adding other compounds (controls) or with the addition of thecompounds under examination.

Table II below gives the percentage values of the contractile force ofthe heart, showing a positive inotropic effect, calculated after 10minutes from the interruption of the anoxic period (myocardialrestoration).

The antiarrhythmic effect of the compounds was also investigated in miceaccording to the P. W. Nwangwu, T. Holcslow procedure (P. W. Nwangwu, T.L. Holcslow; Arch. Int. Pharmacodyn. 229, 219 (1977)). Using aconitine(5 γ/ml) as arrhythmogenic agent, the changes in the cardiac rhythm ofthe animals were recorded and the onset time of initial arrhythmiaand/or of ventricular tachycardia were used as end point. The resultsare summarized in Table III.

The effect of the compounds on the modification of the lipoproteinpattern as well as on the levels of plasma chlolesterol andtriglycerides, altered by oral administration of olive oil, wasinvestigated in normally fed rats, treated orally with olive oil, 15 mlkg⁻¹, 1 hour before the oral administration of the compound, and withthe compounds at various concentrations.

The most important effect, after two hours from olive administration,which entailed an increase in triglycerides and cholesterol withreduction of α lipoproteins and increase of the β and pre-β fractions,was well antagonized by some compounds which, as shown in Table IV,proved to be able to restore to normal the foregoing parameters widelyreaching the limits of statistical significativity.

                  TABLE I                                                         ______________________________________                                        LD50, mg kg.sup.-1 i.p. in mice of some acyl derivatives of                   general formula (I). Weil method (N = 5,K = 4)                                Compounds         LD50    and fiducial limits                                 ______________________________________                                        acrilyl-CAR       1380    (950-1800)                                          vinyl-CAR         1200    (800-1600)                                          tert-butyl ACAR   1115    (789-1440)                                          cyclohexyl ACAR   850     (572-1128)                                          cyclohexyl-butyryl CAR                                                                          925     (675-1175)                                          2-cyclopenten ACAR                                                                              1200    (850-1550)                                          ethoxyacetyl CAR  760     (545-975)                                           3-carbomethoxypropionyl CAR                                                                     985     (709-1260)                                          2-hydroxy isobutyryl CAR                                                                        1470    (1170-1770)                                         2-hydroxy isovaleryl CAR                                                                        1585    (1227-1943)                                         formyl propionyl CAR                                                                            1010    (850-1170)                                          ethoxy ACAR       2120    (1820-2420)                                         methoxy ACAR      1980    (1630-2330)                                         monomethylglutaryl CAR                                                                          1870    (1620-2120)                                         ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Effect of some acyl derivatives of carnitine, having general                  formula (I) on the contractile force of rabbit's heart "in vitro".                                      contractile                                                                   force                                                                concen-  mean ±                                           Compounds        tration  ESM        P                                        ______________________________________                                        Krebs. (control) --       26.93 ± 5.31                                     acrilyl CAR      10.sup.-6 M                                                                            55.31 ± 4.36                                                                          ≦0.01                             vinyl CAR        10.sup.-6 M                                                                            48.25 ± 5.12                                                                          ≦0.01                             tert-butyl ACAR  10.sup.-6 M                                                                            59.33 ± 5.26                                                                          ≦0.001                            cyclohexyl ACAR  10.sup.-6 M                                                                            43.18 ± 4.81                                                                          ≦0.05                             cyclohexyl butyryl CAR                                                                         10.sup.-6 M                                                                            42.15 ± 4.17                                                                          ≦0.05                             2-cyclopentenyl ACAR                                                                           10.sup.-6 M                                                                            59.83 ± 3.26                                                                          ≦0.01                             ethoxyacetyl CAR 10.sup.-6 M                                                                            62.25 ± 3.24                                                                          ≦0.01                             3-carbomethoxypropionyl CAR                                                                    10.sup.-6 M                                                                            70.35 ± 5.23                                                                          ≦0.001                            2-hydroxy isobutyryl CAR                                                                       10.sup.-6 M                                                                            73.88 ± 4.12                                                                          ≦0.001                            2-hydroxy isovaleryl CAR                                                                       10.sup.-6 M                                                                            82.53 ± 4.09                                                                          ≦0.001                            formyl propionyl CAR                                                                           10.sup.- 6 M                                                                           74.26 ± 4.15                                                                          ≦0.001                            ethoxy ACAR      10.sup.-6 M                                                                            78.15 ± 3.12                                                                          ≦0.001                            methoxy ACAR     10.sup.-6 M                                                                            81.25 ± 4.08                                                                          ≦0.001                            monomethylglutaryl CAR                                                                         10.sup.-6 M                                                                            58.12 ± 4.25                                                                          ≦0.01                             ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Effect of some acyl derivatives of carnitine having general                   formula (I) on the arrythmia induced by Aconitine in mice. %                  increase of the latency time to onset of initial cardiac arrythmia            and tachycardia with respect to the control group.                                          concen-                                                                       trations                                                                      mg kg.sup.-1                                                                         latency time for                                         Compounds       i.v.     arrythmias                                                                              tachycardia                                ______________________________________                                        acryl CAR       50       45        39                                         vinyl CAR       38       53        41                                         tert-butyl ACAR 25       59        36                                         cyclohexyl ACAR 35       63        44                                         cyclohexyl butyryl ACAR                                                                       50       48        32                                         cyclopentenyl ACAR                                                                            100      40        20                                         ethoxyacetyl CAR                                                                              100      40        20                                         3-carbomethoxy propionyl                                                                      25       65        39                                         CAR                                                                           2-hydroxy isobutyryl CAR                                                                      25       55        48                                         2-hydroxy isovaleryl CAR                                                                      40       60        30                                         formyl propionyl CAR                                                                          60       55        34                                         ethoxy ACAR     20       60        55                                         methoxy ACAR    25       65        50                                         monomethylglutaryl CAR                                                                        30       52        40                                         Quinidine       8.9      50        41.7                                       ______________________________________                                    

                                      TABLE IV                                    __________________________________________________________________________    Effect of some acyl-carnitine derivatives of general formula (I) on           plasma cholesterol (Chol.)                                                    lipoproteins in rats treated with olive oil, pre-β                       15 ml kg.sup.-1 orally, 1 hour before compound administration                 __________________________________________________________________________                                   TG          Chol.                              Compounds        mg kg.sup.-1                                                                       oil ml kg.sup.-1                                                                       mg/100 ml   mg/100 ml                          __________________________________________________________________________    Blank            --   --       75.12 ± 6.15                                                                           65.15 ± 6.18                    Control          --   15       215.36 ± 20.18                                                                         96.18 ± 4.16                    vinyl CAR        300  15       112.15 ± 15.16n.s.                                                                     78.15 ± 6.16n.s.                tert-butyl CAR   350  15       99.36 ± 10.12                                                                          70.12 ± 3.24Δ             cyclohexyl CAR   400  15       100.12 ± 15.16Δ                                                                  85.15 ±4.26n.s.                 3-carbomethoxypropionyl CAR                                                                    350  15       88.15 ± 15.36                                                                          69.25 ± 3.26                    2-hydroxy isobutyryl CAR                                                                       450  15       100.29 ± 12.48                                                                         75.03 ± 4.12Δ             ethoxy ACAR      250  15       78.25 ± 10.12                                                                          70.26 ± 6.48                    methoxy ACAR     300  15       85.14 ± 13.26                                                                          72.12 ± 6.87                    monomethylglutaryl CAR                                                                         400  15       120.36 ± 81.27 ± 5.92                    __________________________________________________________________________                                               n.s.                                                         % Lipoproteins                                      Compounds      mg kg.sup.-1                                                                       oil ml kg.sup.-1                                                                    α  β   pre-β                        __________________________________________________________________________    Blank          --   --    36.15 ± 2.12                                                                        10.15 ± 1.23Δ                                                                 49.22 ± 2.17Δ            Control        --   15    23.28 ± 2.19                                                                        16.12 ± 1.48                                                                        56.45 ± 2.36                   vinyl CAR      300  15    29.46 ± 3.15n.s.                                                                    14.13 ± 1.63n.s.                                                                    48.89 ± 2.96n.s.               tert-butyl CAR 350  15    31.12 ± 2.17□                                                            13.27 ± 1.12□                                                            51.36 ± 2.11□       cyclohexyl CAR 400  15    36.48 ± 2.36                                                                        12.15 ± 1.09                                                                        49.12 ± 2.17Δ            3-carbomethoxypropionyl CAR                                                                  350  15    34.17 ± 3.23                                                                        11.18 ± 1.15                                                                        50.03 ± 2.09Δ            2-hydroxy isobutyryl CAR                                                                     450  15    27.19 ± 3.48n.s.                                                                    10.36 ± 1.12                                                                        48.36 ± 1.15                   ethoxy ACAR    250  15    37.15 ± 2.17                                                                        10.28 ± 1.52                                                                        42.15 ± 2.27                   methoxy ACAR   300  15    36.39 ± 3.12                                                                        12.32 ± 1.65                                                                        45.83 ± 3.46                   monomethylglutaryl CAR                                                                       400  15    35.28 ± 3.94n.s.                                                                    14.25 ± 1.83n.s.                                                                    51.12 ± 4.15n.s.               __________________________________________________________________________     Student "t" test for the difference with respect to the control               □, Δ e   indicate respectively P ≦0.05, 0.01 and      0.001. N = 6                                                             

PHARMACEUTICAL PREPARATIONS

1. Solutions and sterile aqueous solutions containing acyl-carnitines offormula (I) in concentrations from 25 mg to 500 mg per ml.

(a) The excipient for injectable ampoules/vials is prepared inaccordance with the following non-limitative composition:

    ______________________________________                                        sodium carboxymethyl cellulose                                                                     10       mg/ml                                           (at low viscosity)                                                            polysorbate 80       4        mg/ml                                           propylparaben        0.4      mg/ml                                           water for injections sufficient for 1 ml, 2 ml, 5 ml                          and 10 ml ampoules/vials                                                      ______________________________________                                    

(b) The excipient for phleboclysis bottles containing 50 ml, 100 ml, 250ml, 500 ml and 1000 ml is prepared in accordance with the followingnon-limiting composition:

    ______________________________________                                               NaCl  8.6            g/l                                                      KCl   0.3            g/l                                                      CaCl.sub.2                                                                          0.33           g/l                                                      water for injections sufficient for 1 liter.                           ______________________________________                                    

(c) The excipient for bottles for oral use containing from 5 ml to 100ml is prepared in accordance with the following non-limitingcomposition:

    ______________________________________                                        mannitol          11         mg/ml                                            sorbitol          600        mg/ml                                            sodium benzoate   3          mg/ml                                            orange extract    200        mg/ml                                            vitamin B.sub.12  3          mcg/ml                                           sufficient purified water                                                     ______________________________________                                    

2. Tablets containing from 20 mg to 500 mg of acyl-carnitine of formula(I). The excipient is prepared in accordance with the followingnon-limiting composition:

    ______________________________________                                                starch                                                                              45%                                                                     avicel                                                                              45%                                                                     talc  10%                                                             ______________________________________                                    

3. Capsules containing from 20 mg to 500 mg of acyl-carnitine of formula(I) without excipients.

4. Aerosol and spray preparations from 500 mg to 10 g of anacyl-carnitine of formula (I). The excipient is prepared in accordancewith the following non-limiting composition:

    ______________________________________                                        ethanol            30%                                                        purified water     30%                                                        sufficient freon 12/114                                                                          (50 parts/50 parts).                                       ______________________________________                                    

What is claimed is:
 1. An acyl-derivative of carntine orpharmaceutically acceptable salt thereof, having the general formula##STR23## wherein x is an anion, and R is the radical of one of thefollowing organic acids: dithiolane 3-pentanoic, or2-thiophenecarboxylic or 2-thiopheneacetic acid.
 2. The acyl derivativesof the carnitine of claim 1 in their optically active forms.
 3. The acylderivatives of the carnitines of claim 1 in the in their racemic form.4. A pharmaceutically acceptable composition for treating cardiacdisorders, hyperlipoproteinaemias and hyperlipidaemias, comprising apharmaceutically acceptable amount of An acyl-derivative of carntine orpharmaceutically acceptable salt thereof, having the general formula##STR24## wherein x is an anion, and R is the radical of one of thefollowing organic acids: dithiolane 3-pentanoic, or2-thiophenecarboxylic or 2-thiopheneacetic acid.